Crystal structure of the human monocyte-activating receptor, "Group 2" leukocyte Ig-like receptor A5 (LILRA5/LIR9/ILT11)

Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2006; 281(28):19536-44. DOI: 10.1074/jbc.M603076200
Source: PubMed


Human leukocyte Ig-like receptor B1 (LILRB1) and B2 (LILRB2) belong to “Group 1” receptors and recognize a broad range of
major histocompatibility complex class I molecules (MHCIs). In contrast, “Group 2” receptors show low similarity with LILRB1/B2,
and their ligands remain to be identified. To date, the structural and functional characteristics of Group 2 LILRs are poorly
understood. Here we report the crystal structure of the extracellular domain of LILRA5, which is an activating Group 2 LILR
expressed on monocytes and neutrophils. Unexpectedly, the structure showed large changes in structural conformation and charge
distribution in the region corresponding to the MHCI binding site of LILRB1/B2, which are also distinct from killer cell Ig-like
receptors and Fcα receptors. These changes probably confer the structural hindrance for the MHCI binding, and their key amino
acid substitutions are well conserved in Group 2 LILRs. Consistently, the surface plasmon resonance and flow cytometric analyses
demonstrated that LILRA5 exhibited no affinities to all tested MHCIs. These results raised the possibility that LILRA5 as
well as Group 2 LILRs do not play a role in any MHCI recognition but could possibly bind to non-MHCI ligand(s) on the target
cells to provide a novel immune regulation mechanism.

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    • "Both LILRB1 and LILRB2 of Group 1 LILRs have these crucial residues in the D1 domain and truly bind to at least 3 alleles of classical and non-classical HLAIs [20]. Meanwhile, LILRA2 [18] as Group 1 LILRs, and LILRB4 [21] and LILRA5 [22] as Group 2 LILRs have no these residues in the D1 domain. Indeed, there is no so called “hydrophobic core” by strands-helices transition in the D1 domain of these LILRs. "
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    ABSTRACT: Structurally, Group 1 LILR (Leukocyte Immunoglobulin (Ig)-Like Receptor, also known as Ig-like transcripts, ILT; Leukocyte Ig-like receptor, LIR; and CD85) members are very similar in terms of the HLAIs (human leukocyte antigen class I molecules) binding region and were hypothesized that they all bind to HLAIs. As one of the Group 1 LILRs, LILRA3 is the only secretory LILR and may greatly control the inhibitory immune response induced by LILRB1, LILRB2, and other HLA-binding LILR molecules like LILRA1. Nevertheless, little was known about the binding of LILRA3 to HLAIs. In this report, we present the crystal structure of the LILRA3 domain 1 (D1) and evaluate the D1 and D1D2 (domain 1 and domain 2) binding to classical and non-classical HLAIs using BIAcore® surface plasmon resonance analysis (SPR). We found that LILRA3 binds both classical HLA-A*0201 and non-classical HLA-G1 but with reduced affinities compared to either LILRB1 or LILRB2. The polymorphic amino acids and the LILRA3 D1 structure support this notion.
    Full-text · Article · Apr 2011 · PLoS ONE
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    • "However, the ligands for the stimulatory group of ILTs are largely unknown (Cosman et al., 1997; Brown et al., 2004). Structural analysis revealed significant differences in MHC class I–binding sites between the inhibitory and stimulatory ILTs (Shiroishi et al., 2006), suggesting distinct ligand recognition by the two groups of ILTs. Here, we used a NFAT-GFP reporter cell system that reliably senses ILT7 surface ligation in the presence of an ILT7 ligand, which led to the positive identification of BST2, a glycoprotein unrelated to the MHC molecules. "
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    ABSTRACT: Plasmacytoid dendritic cells (pDCs) produce copious type I interferon (IFN) upon sensing nucleic acids through Toll-like receptor (TLR) 7 and TLR9. Uncontrolled pDC activation and IFN production are implicated in lymphopenia and autoimmune diseases; therefore, a mechanism controlling pDC IFN production is essential. Human pDCs specifically express an orphan receptor, immunoglobulin-like transcript 7 (ILT7). Here, we discovered an ILT7 ligand expressed by human cell lines and identified it as bone marrow stromal cell antigen 2 (BST2; CD317). BST2 directly binds to purified ILT7 protein, initiates signaling via the ILT7-FcepsilonRIgamma complex, and strongly inhibits production of IFN and proinflammatory cytokines by pDCs. Readily induced by IFN and other proinflammatory cytokines, BST2 may modulate the human pDC's IFN responses through ILT7 in a negative feedback fashion.
    Full-text · Article · Jul 2009 · Journal of Experimental Medicine
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    ABSTRACT: HLA-G is a nonclassical MHC class I (MHCI) molecule that can suppress a wide range of immune responses in the maternal-fetal interface. The human inhibitory immune receptors leukocyte Ig-like receptor (LILR) B1 [also called LIR1, Ig-like transcript 2 (ILT2), or CD85j] and LILRB2 (LIR2/ILT4/CD85d) preferentially recognize HLA-G. HLA-G inherently exhibits various forms, including beta(2)-microglobulin (beta(2)m)-free and disulfide-linked dimer forms. Notably, LILRB1 cannot recognize the beta(2)m-free form of HLA-G or HLA-B27, but LILRB2 can recognize the beta(2)m-free form of HLA-B27. To date, the structural basis for HLA-G/LILR recognition remains to be examined. Here, we report the 2.5-A resolution crystal structure of the LILRB2/HLA-G complex. LILRB2 exhibits an overlapping but distinct MHCI recognition mode compared with LILRB1 and dominantly recognizes the hydrophobic site of the HLA-G alpha3 domain. NMR binding studies also confirmed these LILR recognition differences on both conformed (heavy chain/peptide/beta(2)m) and free forms of beta(2)m. Binding studies using beta(2)m-free MHCIs revealed differential beta(2)m-dependent LILR-binding specificities. These results suggest that subtle structural differences between LILRB family members cause the distinct binding specificities to various forms of HLA-G and other MHCIs, which may in turn regulate immune suppression.
    Full-text · Article · Nov 2006 · Proceedings of the National Academy of Sciences
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